Effective treatments for substance abuse disorders, such as Methamphetamine (Meth) addiction, remain a major unmet medical need. Meth addiction is intimately related to dopamine-based rewards. The neurotensin 1 receptor (NTR1) is found among dopamine neurons in the CNS. Though evidence points towards NTR1 as a molecular target for treating psychostimulant-based drug addiction, particularly meth abuse, few non-peptide neurotensin agonists have been identified, and none that are brain penetrant. Recently, we discovered a series of brain penetrant NTR1 agonists. Our goal is to provide an orally active pre-clinical drug based on our NTR1 agonist lead series developed through the NIH's MLPCN program to treat Meth addiction. R21 Phase: We propose a preliminary SAR expansion to show tractability around the SAR of the lead compound. To accomplish this, we will: SA 1: Design and synthesize optimized orally active (in vivo) NTR1 agonists. We will synthesize 100-150 new analogs around ML314 to optimize the potency, selectivity and pharmacokinetic (PK) properties of the lead NTR1 agonists. SA 2: Assess the potency and selectivity of NTR1 agonists. We will evaluate compounds synthesized in our primary high content assay and NTR2 counter screen. SA 3: Evaluate novel NTR1 agonists using in vitro ADME/T and in vivo PK assays, including brain penetration. Compounds meeting potency and selectivity criteria will be evaluated for their solubility, permeability (including BBB permeabiliy), protein binding, and plasma/microsomal stability. The most promising compounds will be examined for their rodent PK (mouse/rat), including brain levels. R33 Phase: We propose a full lead optimization campaign with the goal of delivering a lead and several backups. To achieve this, we will: SA 1: Design and synthesize optimized orally active (in vivo) NTR1 agonists. We will synthesize 350-400 new analogs around ML314 to optimize the potency, selectivity and PK properties of the lead NTR1 agonists. SA 2: Assess the potency and selectivity of NTR1 agonists in relevant in vitro assays. We will evaluate compounds synthesized in R33-SA1 in physiochemical, toxicology and receptor pharmacology assays to identify a lead candidate and at least one backup. SA 3: Evaluate novel NTR1 agonists using in vitro ADME/T and in vivo PK assays, including brain penetration. Perform initial preclinical studies on selected NTR1 agonist new chemical entities. We will evaluate compounds meeting criteria for solubility, permeability (including BBB), protein binding, and plasma/microsomal stability. The most promising compounds will be examined for their rodent PK (mouse/rat), including brain levels. Preliminary preclinical studies will be performed on the selected lead and back ups. SA 4: Characterize lead NTR1 agonists in rodent models of drug addiction. We will profile lead agonists in the mouse dopamine transporter knockout model, with conditioned place preference and self-administration model of meth addiction. The overall objective is to identify an orally available, development-ready NTR1 agonist, which is efficacious in all models.